Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is a debilitating syndrome with no known cause. People with ME/CFS suffer profound fatigue that is markedly worsened by physical or mental activity and generally report a variety of other symptoms such as problems with sleep, thinking and various forms of body pain. Over one million Americans experience symptoms compatible with the syndrome and many suffer high levels of disability. Most past searches for microbial triggers or for immunological problems have depended on testing for a finite number of parameters. This is much like playing the parlor game of Twenty questions in which one has only so many questions before the game is up. We propose to take a fresh look at why people with ME/CFS feel profoundly tired following exercise by applying newly available gene sequencing technologies with standardized exercise testing. The exercise testing provides a measured stimulus and also allows objective categorization of patients according to their exercise response. The next generation sequencing will allow a much deeper probe of host gene expression (especially as it relates to immune signaling after exercise) than has previously been possible. By looking for differences in those with ME/CFS and in healthy people before and after exercise challenge, we hope to identify specific patterns or response that might explain prolonged fatigue symptoms, help with diagnosis and point to pathways for therapy.